Genetic regulatory mechanisms in the synthesis ..

Genetic regulatory mechanisms in the synthesis of proteins

A summary of bacterial protein toxins and their activities is givenin Tables 4. Details of the mechanisms of action of these toxins andtheirinvolvementin the pathogenesis of disease is discussed in chapters with thespecificbacterial pathogens.

Mechanisms of Protein Synthesis by the Ribosome

Telomerase is suppressed in the majority of somatic cells leading to the continuing telomere attrition, which leads to irreversible cell-cycle arrest known as replicative cell senescence. It has been demonstrated that primary human fibroblasts that have lost the ability to senesce, display telomere shortening and eventually enter a crisis stage that culminates in chromosome fusion, aneuploidy and cell death (Counter et al., 1992). It has been proposed that it is therefore important for cancer cells to regain the ability to maintain telomeres, in order to avoid senescence and extensive chromosome fusion during crisis (Counter et al., 1992; Harley, 1995). In fact it has been shown that about 85-90% of human cancers have reactivated telomerase and are able to maintain telomere length (Jefford and Irminger-Finger, 2006). Interestingly cancer cells that are deficient for telomerase activity are able to maintain telomere length via a mechanism known as alternative lengthening of telomeres or ALT. It has been suggested that the ALT mechanism makes use of DNA repair pathways and recombination to maintain telomere length (Reddel, 2003). Thus, whichever mechanism employed by the cell, it appears that maintaining telomere length is critical for tumourigenesis and cellular immortalization (Jefford and Irminger-Finger, 2006). Telomere maintenance is also required for chromosomal instability. Given that cancer cells inevitably display properties of telomere maintenance and genetic instability, it has been proposed that telomere loss could be either a cause or a consequence of genetic instability (Jefford and Irminger-Finger, 2006), or perhaps be involved in both.

The regulatory mechanisms in branched-chain amino acid synthesis were compared between 2-thiazolealanine (2-TA) resistant L-leucine and L-valine producing mutants and the 2-TA sensitive original strains of 2256. In the original strains, sensitive to 2-TA, α-isopropylmalate (IPM) synthetase, the initial enzyme specific for L-leucine synthesis, is sensitive to feedback inhibition and to repression by L-leucine, and α-acetohydroxy acid (AHA) synthetase, the common initial enzyme for synthesis of L-isoleucine, L-valine as well as L-leucine, is sensitive to feedback inhibition by each one of these amino acids, and to repression by them all. In strain No. 218, a typical L-leucine producer resistant to 2-TA, IPM synthetase was found to be markedly desensitized and derepressed, and AHA synthetase remained unaltered. On the contrary, in strain No. 333, L-valine producer resistant to 2-TA, AHA synthetase was found to be desensitized and partially derepressed, and IPM synthetase remained unaltered. The genetic alteration of these regulatory mechanisms was discussed in connection with the accumulation pattern of amino acids.

Genetic Regulatory Mechanisms in the Fungi

It is the interplay between histone acteylases (HATs) and histone deacetylates (HDACs) that determine the precise balance of acetylation within the nucleus. Abnormal HDAC activity has been commonly observed in (Espino et al., 2005). Studies done in these cancers have shown that fusion proteins such as and can recruit HDACs, which in turn lead to aberrant transcriptional repression that halts differentiation (de Ruijter et al., 2003; Hong et al., 1997). It has been proposed that a dynamic relationship exists between histone modifications, chromatin structure and DNA methylation (Szyf et al., 2004; Ting et al., 2004). For example it has been shown that histone acetylation and gene activation, results in DNA demethylation (Szyf et al., 2004), while the opposite situation where low steady state level of histone acetylation and methylation, results in the recruitment of DNMT1 and DNA methylation of regulatory regions (Espino et al., 2005). Thus, it is mechanistically possible that skewed regulation of this inter-relationship could lead to genetic instability.

Genetic Regulatory Mechanisms in the Synthesis of ..

CpG islands commonly occur in the promoter regions, thus hypermethylation of this region has been shown to silence gene expression (Bird, 2002). This was first identified in the retinoblastoma protein () followed by promoter hypermethylation of several other tumour suppressor and cell-cycle regulatory genes (Greger et al., 1989). It is believed that hypermethylation too is an early event that may precede the neoplastic process (Momparler, 2003; Nephew and Huang, 2003). A prime example of the role of hypermethylation in contributing to genetic instability is hMLH1 inactivation, where promoter hypermethylation is thought to be primarily responsible for approximately 15% of sporadic colorectal cancers associated with microsatellite instability (Kane et al., 1997; Herman et al., 1998). In a study by Costello et al. (Lander et al., 2001), 1184 unselected CpG islands were screened in 98 primary human tumours using restriction landmark genomic scanning (RLGS). This study found that on average about 600 CpG islands were aberrantly methylated in tumours, indicating the potentially vast number of genes likely to be aberrantly expressed due to this mechanism.

GENETIC REGULATION OF DEVELOPMENT AND AFLATOXIN SYNTHESIS IN ..

One mechanism that can bring about chromosomal instability (CIN) is telomere loss. Although CIN is not addressed in detail in this paper, the role of is briefly summarized to highlight the important role it may play in carcinogenesis and the implications it may have in the field of genetic instability.

Germline mutations in the MMR genes are associated with the inherited cancer syndrome, . Instability of microsatellite repeats is seen in tumours of as many as 85% of patients with HNPCC, making it a hallmark feature of this syndrome (Aaltonen et al., 1993; Aaltonen et al., 1994). HNPCC, which accounts for about 2% of all CRC cases, is one of the most common cancer predisposition syndromes. It is an autosomal dominant disorder characterized by the development of cancer in the colon as well as in extra-colonic sites including the endometrium, stomach, urinary tract, ovaries, small bowel and brain. MMR deficiency has also been shown to give rise to , and gastric cancers. Defective mismatch repair increases the likelihood of mutations in genes containing repeat sequences that regulate growth, differentiation or apoptosis. Somatic mutations of several genes including TGFBR2, BAX, TCF4, AXIN2, and PTEN are found in MSI positive cancers.

... capable of interacting with the promoter that drives its own production or promoters of other genes. Such transcriptional regulation is the typical method utilized by cells in controlling expression =-=[42, 43]-=-, and it can occur in a positive or negative sense. Positive regulation, or activation, occurs when a protein increases transcription through biochemical reactions that enhance polymerase binding at t...

The regulation of synthesis and secretion of many bacterial toxinsistightly controlled by regulatory elements that are sensitive toenvironmentalsignals. For example, the production of diphtheria toxin is totallyrepressedby the availability of adequate amounts of iron in the medium forbacterialgrowth. Only under conditions of limiting amounts of iron in the growthmedium does toxin production become derepressed. The expression ofcholeratoxin and related virulence factors (adhesins) is controlled byenvironmentalosmolarity and temperature. In , induction ofdifferentvirulence components is staggered, such that attachment factors areproducedinitially to establish the infection, and toxins are synthesized andreleasedlater to counter the host defenses and promote bacterial survival.

REGULATORY MECHANISMS FOR SYNTHESIS OF ..

...transcribed. It is also increasingly evident that RNA itself can and does have a very wide repertoire of biological functions (1) and, in particular—as first predicted by Jacob and Monod 45 years ago =-=(2)-=-—that it is widely employed as a means of gene regulation, both in cis and in trans, especially in the higher eukaryotes. These RNAs are the subject of this review. EXPANSION OF ncRNAs AND RNA METABOL...

Genetic Regulatory Mechanisms in the Fungi - Annual …

The tumour microenvironment has been proposed to contribute to the increased genetic instability seen in cancer cells. Several studies have lent support to this notion, including a study that demonstrated a higher rate of genomic instability of mouse cells when grown in vivo as subcutaneous tumour implants in syngeneic mice, as measured using an EGFP reporter gene and a genomic minisatellite locus (Li et al., 2001). More specifically, hypoxia has been singled out as a major microenvironmental factor. Hypoxia, which appears to occur transiently within the tumour microenvironment, has been shown to lead to cycles of hypoxia and reoxygenation (Bindra and Glazer, 2005). This is thought to lead to DNA damage as a result of reactive oxygen species (ROS) and the enzyme superoxide dismutase. In addition to ROS leading to the formation of 8-oxoG, and accumulating evidence suggest a role for oxygen and ROS in causing single and (Bindra and Glazer, 2005). In addition to its ability to cause aberrations in DNA, these cycles of hypoxia and reoxygenation have been shown to affect DNA synthesis, by both interrupting this process and by leading to over-replication after reoxygenation (Bindra and Glazer, 2005; Cuvier et al., 1997; Young. and Hill, 1990; Young et al., 1990). Other studies have found that it is hypoxia induced gene amplification of p-Glycoprotein that is responsible for the observed resistance to adriamycin and doxorubicin (Luk et al., 1990; Rice et al., 1987), indicating that gene amplification may also be caused by hypoxia. Furthermore, emerging evidence suggests that hypoxia can influence the integrity of the genome by impacting upon DNA repair pathways. As described above, MLH1 is one of the key genes involved in mismatch repair. It was shown that hypoxia downregulates the expression of the MLH1 gene at the transcriptional level and this was thought to occur via chromatin remodeling, as treatment with an histone deacteylase inhibitor prevented the aforementioned decrease (Mihaylova et al., 2003). It has also been demonstrated that hypoxia enriches for MMR deficient cells (Hardman et al., 2001). Thus, DNA damage, defective DNA synthesis, gene amplification and the deregulation of DNA repair pathways all appear to be mechanisms by which hypoxia contributes to genetic instability. Little is still known about other microenvironmental factors that may lead to instability. However, it has been suggested that the tumour microenvironment may represent in mammalian cells a conserved evolutionary mechanism that increases the rate of mutation in response to cellular stresses, which preferentially gives cancer cells a survival advantage (Bindra and Glazer, 2005).